Copeptin for risk stratification in non-traumatic headache in the emergency setting: a prospective multicenter observational cohort study.

BACKGROUND: In the emergency setting, non-traumatic headache is a benign symptom in 80% of cases, but serious underlying conditions need to be ruled out. Copeptin improves risk stratification in several acute diseases. Herein, we investigated the value of copeptin to discriminate between serious secondary headache and benign headache forms in the emergency setting. METHODS: Patients presenting with acute non-traumatic headache were prospectively enrolled into an observational cohort study. Copeptin was measured upon presentation to the emergency department. Primary endpoint was serious secondary headache defined by a neurologic cause requiring immediate treatment of the underlying disease. Secondary endpoint was the combination of mortality and hospitalization within 3 months. Two board-certified neurologist blinded to copeptin levels verified the endpoints after a structured 3-month-telephone interview. RESULTS: Of the 391 patients included, 75 (19%) had a serious secondary headache. Copeptin was associated with serious secondary headache (OR 2.03, 95%CI 1.52-2.70, p < 0.0001). Area under the curve (AUC) for copeptin to identify the primary endpoint was 0.70 (0.63-0.76). After adjusting for age > 50, focal-neurological abnormalities, and thunderclap onset of symptoms, copeptin remained an independent predictive factor for serious secondary headache (OR 1.74, 95%CI 1.26-2.39, p = 0.001). Moreover, copeptin improved the AUC of the multivariate logistic clinical model (p-LR-test < 0.001). Even though copeptin values were higher in patients reaching the secondary endpoint, this association was not significant in multivariate logistic regression. CONCLUSIONS: Copeptin was independently associated with serious secondary headache as compared to benign headaches forms. Copeptin may be a promising novel blood biomarker that should be further validated to rule out serious secondary headache in the emergency department. TRIAL REGISTRATION: Study Registration on 08/02/2010 as NCT01174901 at clinicaltrials.gov.

Scalp defect repair: a comparative analysis of different surgical techniques.

Scalp defects often arise in multimorbid patients. This study aimed at establishing an algorithm of defect repair with particular focus on new regenerative options.All patients, who consulted to the Department of Oral and Maxillofacial Surgery/Plastic Surgery, University Jena between April 2005 and March 2010 were reviewed. Different reconstructive options were compared with regard to duration of hospital stay as well as rate of reoperations needed to achieve full closure.Sixty-eight patients were identified. Local flaps were more effective than skin grafts (P = 0.038) and microvascular free flaps (P = 0.037) in case of skin-galea-periosteal-defects. However, no differences were found between skin grafting in combination with wound bed preconditioning using a dermal regeneration template and microvascular free flap transfer. Scalp defects should be repaired based on careful evaluation of defect anatomy as well as patient's general health. Application of dermal regeneration templates allows for an increase of the indication spectrum of free skin grafts.

Analysis of inflammatory periimplant lesions during a 12-week period of undisturbed plaque accumulation--a comparison between flapless and flap surgery in the mini-pig.

This study's aim was to clarify the influence of soft tissue management on the development of periimplant infection. Four weeks after removal of all maxillary premolars in 12 mini-pigs, four BEGO Semados RI implants were inserted in each maxillary quadrant. Employing a split-mouth design, one quadrant was randomized to flapless insertion while the contralateral side was chosen for flap surgery. Following 1, 2, 4 and 12 weeks of transmucosal implant, healing biopsies were retrieved from the periimplant soft tissue and subjected to further analysis. Histomorphometrically, a significant reduction of transmigration of polymorphonuclear neutrophils (week 1, p = 0.007; week 2, p = 0.021; week 4, p = 0.023; week 12, p = 0.013) as well as the density of the subepithelial inflammatory infiltrates (week 1, p = 0.007; week 2, p = 0.046; week 4, p = 0.003; week 12, p = 0.032) was verified following flapless surgery. Quantification of inducible nitric oxide synthase showed significantly reduced expression in the flapless group 2 (p = 0.027), 4 (p = 0.005) and 12 (p = 0.004) weeks post-insertion. Analysis of CD31 and collagen I immunostained sections revealed more regular capillary distribution as well as higher vessel and collagen density in the flapless group. The data of the present study indicate that flapless placement reduces the incidence of inflammatory periimplant soft tissue lesions during a 12-week period. Considering the beneficial effects of flapless placement on early soft tissue healing and stability, the technique might be preferred in case of an uncomplicated locoregional anatomy with sufficient hard and soft tissue. However, this positive effect might disappear after manipulation of the implant and soft tissue during impression taking or try in of the prosthodontic supraconstruction.

The susceptibility loci juvenile idiopathic arthritis shares with other autoimmune diseases extend to PTPN2, COG6, and ANGPT1.

OBJECTIVE: To test for associations between non-major histocompatibility complex susceptibility loci previously reported in autoimmune diseases and juvenile idiopathic arthritis (JIA). METHODS: Published autoimmune disease genome-wide association studies were reviewed, and 519 single-nucleotide polymorphisms (SNPs) were selected for association testing. The initial cohort included 809 JIA cases and 3,535 controls of non-Hispanic, European ancestry. Of the SNPs, 257 were successfully genotyped, while 168 were imputed with quality. Based on findings in the initial cohort, replication was sought for 21 SNPs in a second cohort of 1,015 JIA cases and 1,569 controls collected in the US and Germany. For the initial cohort, tests for association were adjusted for potential confounding effects of population structure by including principal components derived from a genome-wide association study as covariates in logistic regression models. Odds ratios (ORs) and 95% confidence intervals were calculated. RESULTS: Testing for association of previously reported autoimmune disease genetic associations in the initial cohort suggested associations with JIA in 13 distinct loci. Of these, 7 were validated in the replication cohort. Meta-analysis results for the replicating loci included PTPN22 (rs6679677 [OR 1.58, P = 1.98 × 10(-12) ], rs2476601 [OR 1.64, P = 1.90 × 10(-13) ], and rs2488457 [OR 1.32, P = 6.74 × 10(-8) ]), PTPN2 (rs1893217 [OR = 1.33, P = 1.60 × 10(-9) ] and rs7234029 [OR 1.35, P = 1.86 × 10(-10) ]), ADAD1-IL2-IL21 (rs17388568 [OR 1.24, P = 1.13 × 10(-6) ] and rs13143866 [OR 0.83, P = 1.95 × 10(-4) ]), STAT4 (rs3821236 [OR = 1.27, P = 2.36 × 10(-6) ] and rs7574865 [OR = 1.31, P = 2.21 × 10(-6) ]), C12orf30 (rs17696736 [OR = 1.19, P = 2.59 × 10(-5) ]), COG6 (rs7993214 [OR = 0.76, P = 1.10 × 10(-5) ]), and ANGPT1 (rs1010824 [OR = 0.79, P = 2.91 × 10(-4) ]). These polymorphisms have been reported in diseases such as rheumatoid arthritis, type 1 diabetes mellitus, Crohn's disease, and multiple sclerosis. CONCLUSION: General susceptibility loci for autoimmunity are shared across diseases, including JIA, suggesting the potential for common therapeutic targets and mechanisms.

Microvascular free flaps for mandibular reconstruction in Goldenhar syndrome.

Although Goldenhar syndrome is a relatively common craniofacial malformation, there is some debate regarding the ideal treatment of severe mandibular hypoplasia. Traditionally, patients with severe mandibular deficits have been treated with iliac or costochondral bone grafts followed by distraction osteogenesis, with mixed results. The authors present their experience with the use of the osteocutaneous fibula and scapula free flap for mandibular reconstruction in patients with severe mandibular hypoplasia. The cases of 4 patients who underwent free-flap reconstruction of a severely hypoplastic mandible due to Goldenhar syndrome are presented. Microvascular reconstruction of the severely hypoplastic mandible is possible with the osteocutaneous scapula and the fibula flap. Minimal donor-site morbidity is elicited. Furthermore, the vertical relationship can be restored adequately, and breathing is facilitated. The microvascular fibula and scapula flap are a viable option for reconstruction of the severely hypoplastic mandible in patients with Goldenhar syndrome.

Angiogenic gene-modified fibroblasts for induction of localized angiogenesis.

BACKGROUND: Induction of localized angiogenesis is of particular interest in the field of plastic surgery. Topical application of recombined vascular endothelial growth factor (VEGF) shows only little effect on graft healing. This study describes the establishment of an ex vivo engineered VEGF slow release system based on autogenous fibroblasts. METHODS: Primary fibroblasts were subjected to nucleofection and analyzed for transgene expression 1, 2, 3, 4, 7, and 9 d post-nucleofection using FACS. VEGF transgene expression was measured in cell culture supernatants using ELISA. Transgenic protein functionality was examined in the HUVEC proliferation assay. The effect of VEGF transgene expression on the neovascularization of a collagen membrane was investigated in a rat model. RESULTS: Primary fibroblasts were nucleofected with an efficiency of 63.331% and transgene expression showed persistence up to day 9 post-nucleofection. VEGF was expressed in the cell culture up to day 14 with an expression peak at day 3. The cytokine was functionally active. VEGF transgene was released in vivo at day 7 and enhanced neovascularization of a collagen membrane. CONCLUSIONS: Nucleofection is the ideal nonviral tool to engineer transgenic primary fibroblasts for transplantation purpose in an ex vivo gene therapeutic approach. Such ex vivo gene therapy is safe and efficient. Its suitability should be further evaluated in more complex flap models, for example the transfer of a free myocutaneous gracilis flap in the pre-irradiated neck region.

Transgenic overexpression of VEGF164 enhances topical neoangiogenesis without detectable local or systemic side effects.

Various routes of administration have been used for delivering angiogenic genes to ischemic regions. A previous, preliminary study proved the feasibility of in vivo neoangiogenesis stimulation by ex vivo vascular endothelial growth factor (VEGF)-transduced fibroblasts. Taking this into account our aim was to validate therapeutical efficacy of this approach and to investigate potential side effects.Allogenous collagen membranes were implanted at the groin in 30 Wistar rats. Either untransfected, GFP- or VEGF-transfected fibroblasts were injected at the implantation site at the time of surgery. Biopsies were obtained from the membranes, surrounding connective tissue, brain, lung, liver and blood at days 7 and 14 post operation. Samples were investigated for distribution of GFP-positive cells, VEGF-expression, and vessel architecture.Transgenic fibroblasts remained at the site of injection and showed no trafficking into blood or organs. VEGF-overexpression was detectable and resulted in enhanced neovascularization of the membranes. Vessel pathologies were neither detectable in the membrane nor the surrounding tissue.

Apoptosis-related Proteins Are Altered by Selective Tyrosine Kinase Inhibitors and Everolimus in HPV-dependent SCC.

BACKGROUND: Head and neck squamous cell cancer (HNSCC) affects the oral cavity and the pharynx. The aim of the study was to investigate the effects of selective tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, nilotinib and dasatinib and the mammalian target of rapamycin (mTOR) inhibitor everolimus on the expression of apoptosis-related proteins caspase-3, FAS cluster of differentiation (CD)-95 and FAS ligand in human papilloma virus (HPV)-dependent squamous cancer. MATERIALS AND METHODS: Two HPV-negative cell lines (UMSCC-11A/-14C) and one HPV-positive cell line (CERV196) were incubated with TKIs or everolimus and protein concentrations of target proteins were analyzed with enzyme-linked immunosorbent assay (ELISA). RESULTS: Caspase-3 was affected by the tested TKIs in HPV-positive SCC, whereas FAS CD95 and FAS ligand were influenced in HPV-negative SCC. DISCUSSION: This is the first study to analyze the influence of TKIs and everolimus on key proteins of apoptosis. Our results provide novel information contributing to a better understanding of the cell biology of HPV-dependent HNSCC and might contribute to the discovery of novel pharmaceutical treatment strategies for HNSCC.

Combined treatment protocol for temporomandibular joint ankylosis: an observation on a clinical problem.

Various techniques have been defined for the treatment of temporomandibular joint ankylosis. However, in some cases, they are unsuccessful, resulting in continuing pain and limitation in interincisal distance after surgery. This report describes the case of a 32-year-old woman who has been experiencing temporomandibular joint ankylosis for a period of 8 years. Several surgical procedures failed. A treatment approach combining auricular cartilage interposition arthroplasty with postsurgical functional treatment using a spring activator is presented. Using this approach, pain settled and maximal interincisal distance was raised from 22 to 35 mm after 4 months and remained stable for further 10 months.

Influence of static magnetic fields on human myoblast/mesenchymal stem cell co­cultures.

The results of surgical repair of extensive muscle tissue defects are still of primary concern, leaving patients with residual cosmetic and functional impairments. Therefore, skeletal muscle tissue engineering attempts to grow functional neo­tissue from human stem cells to promote tissue regeneration and support defect closure. Despite intensive research efforts, the goal of stable induction of myogenic differentiation in expanded human stem cells by using clinically feasible stimuli, has not yet been reached to a sufficient extent. Therefore, the present study investigated the differentiation potential of static magnetic fields (SMFs), using co­cultures of human satellite cells and human mesenchymal stem cells (MSCs). It has previously been demonstrated that SMFs may act as a promising myogenic stimulus. Tests were performed on co­cultures with and without SMF exposure, using growth medium [high growth factor concentrations (GM)] and differentiation medium [low growth factors concentrations (DM)]. AlamarBlue® assay­based cell proliferation analysis revealed no significant difference between co­cultures with, vs. without SMF stimulation, regardless of growth factor concentrations in the cell culture medium. To determine the degree of differentiation in co­cultures under stimulation with SMFs, semi­quantitative gene expression measurements of the following marker genes were performed: Desmin, myogenic factor 5, myogenic differentiation antigen 1, myogenin, adult myosin heavy chain 1 and skeletal muscle α1 actin. In neither GM nor DM was a steady, significant increase in marker gene expression detected. Verifying the gene expression findings, immunohistochemical antibody staining against differentiation markers revealed that SMF exposure did not enhance myogenic maturation. Therefore, SMF treatment of human satellite cell/MSC co­cultures did not result in the desired increase in myogenic differentiation. Further studies are required to identify a suitable stimulus for skeletal muscle tissue engineering.

Association of adrenal function and disease severity in community-acquired pneumonia.

INTRODUCTION: Rapid and accurate risk stratification in patients with community-acquired pneumonia (CAP) is an unmet clinical need. Cortisol to dehydroepiandrosterone (DHEA) ratio was put forward as a prognostic marker in sepsis. We herein validated the prognostic value of the adrenal hormones DHEA, DHEA-Sulfate (DHEAS), cortisol/DHEA-, cortisol/DHEAS- and DHEA/DHEAS-ratios in patients with CAP. METHODS: We assessed severity of illness using the pneumonia severity index (PSI) and measured adrenal hormone concentrations in 179 serum samples of prospectively recruited patients hospitalized with CAP. We calculated spearman rank correlation, logistic regression analysis and Kaplan Meier curves to study associations of adrenal hormones and outcomes. RESULTS: There was a significant correlation between PSI score and total cortisol (r = 0.24, p = 0.001), DHEAS (r = -0.23, p = 0.002), cortisol/DHEA (r = 0.23, p = 0.003), cortisol/DHEAS (r = 0.32, p = <0.0001) and DHEA/DHEAS (r = 0.20, p = 0.009). In age and gender adjusted logistic regression analysis, cortisol (OR:2.8, 95% CI: 1.48-5.28) and DHEA (OR: 2.62,95% CI: 1.28-5.34), but not DHEAS and the different ratios were associated with all-cause mortality. The discriminatory accuracy of cortisol and DHEA in ROC analysis (area under the curve) was 0.74 and 0.61. In Kaplan Meier analysis, patients in the highest deciles of cortisol and DHEA (p = 0.005 and p = 0.015), and to a lesser extent of cortisol/DHEAS ratio (p = 0.081) had a higher risk of death. CONCLUSION: Cortisol, DHEAS and their ratios correlate with CAP severity, and cortisol and DHEA predict mortality. Adrenal function in severe pneumonia may be an important factor for CAP outcomes.

Analysis of the influence of the macro- and microstructure of dental zirconium implants on osseointegration: a minipig study.

OBJECTIVES: It was the aim of this study to analyze the influence of implant design and surface topography on the osseointegration of dental zirconium implants. STUDY DESIGN: Six different implant designs were tested in the study. Nine or 10 test implants were inserted in the frontal skull in each of 10 miniature pigs. Biopsies were harvested after 2 and 4 months and subjected to microradiography. RESULTS: No significant differences between titanium and zirconium were found regarding the microradiographically detected bone-implant contact (BIC). Cylindric zirconium implants showed a higher BIC at the 2-month follow-up than conic zirconium implants. Among zirconium implants, those with an intermediate Ra value showed a significantly higher BIC compared with low and high Ra implants 4 months after surgery. CONCLUSIONS: Regarding osseointegration, titanium and zirconium showed equal properties. Cylindric implant design and intermediate surface roughness seemed to enhance osseointegration.

Prognostic value of dehydroepiandrosterone-sulfate and other parameters of adrenal function in acute ischemic stroke.

BACKGROUND AND PURPOSE: Acute stroke has a high morbidity and mortality. We evaluated the predictive value of adrenal function testing in acute ischemic stroke. METHODS: In a cohort of 231 acute ischemic stroke patients, we measured dehydroepiandrosterone (DHEA), DHEA-Sulfate (DHEAS), cortisol at baseline and 30 minutes after stimulation with 1 ug ACTH. Delta cortisol, the amount of rise in the 1 ug ACTH-test, was calculated. Primary endpoint was poor functional outcome defined as modified Rankin scale 3-6 after 1 year. Secondary endpoint was nonsurvival after 1 year. RESULTS: Logistic regression analysis showed that DHEAS (OR 1.21, 95% CI 1.01-1.49), but not DHEA (OR 1.01, 95% CI 0.99-1.04), was predictive for adverse functional outcome. Neither DHEA (OR 0.99, 95% CI 0.96-1.03) nor DHEAS (OR 1.10, 95% CI 0.82-1.44) were associated with mortality. Baseline and stimulated cortisol were predictive for mortality (OR 1.41, 95% CI 1.20-1.71; 1.35, 95% CI 1.15-1.60), but only basal cortisol for functional outcome (OR 1.20, 95% CI 1.04-1.38). Delta cortisol was not predictive for functional outcome (OR 0.86, 95% CI 0.71-1.05) or mortality (OR 0.92, 95% CI 0.72-1.17). The ratios cortisol/DHEA and cortisol/DHEAS discriminated between favorable outcome and nonsurvival (both p<0.0001) and between unfavorable outcome and nonsurvival (p = 0.0071 and 0.0029), but are not independent predictors for functional outcome or mortality in multivariate analysis (adjusted OR for functional outcome for both 1.0 (95% CI 0.99-1.0), adjusted OR for mortality for both 1.0 (95% CI 0.99-1.0 and 1.0-1.01, respectively)). CONCLUSION: DHEAS and the cortisol/DHEAS ratio predicts functional outcome 1 year after stroke whereas cortisol levels predict functional outcome and mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT00390962 (Retrospective analysis of this cohort).

A laboratory study comparing the effect of ridge exposure using tissue punch versus mucoperiosteal flap on the formation of the implant-epithelial junction.

OBJECTIVE: The objective of the present study was to clarify the influence of the incision design at the time of implant placement on the consolidation of the implanto-epithelial junction. STUDY DESIGN: Twelve minipigs were chosen for the study. Four weeks after premolar extraction in the maxilla, 4 BEGO Semados RI implants were inserted in each quadrant. Using a split-mouth design, the alveolar crest was exposed by a punch ("flapless surgery") on one side and by a crestal incision ("flap surgery") on the other side. Biopsies were obtained from the peri-implant soft tissue at weeks 1, 2, 4, and 12 postinsertion, respectively, and analyzed for the expression of integrin α(6)ß(4) chain ß(4) (ITGB4) and laminin 5 γ(2) chain (lamc2), 2 important marker molecules for the formation of the implanto-epithelial junction. RESULTS: Following exposure of the alveolar crest by the punch technique, a significantly higher expression of ITGB4 was found at the 2- (P = .009), 4- (P = .001), and 12-week (P = .005) follow-up. Furthermore, the expression of lamc2 was significantly higher following punch exposure after 1 (P = .033), 2 (P = .041), 3 (P = .004), and 12 weeks (P = .002) of transmucosal implant healing. CONCLUSIONS: The data of the present study indicate that flapless placement improved the formation of a sufficient implanto-epithelial junction.

Correlation between clinical findings and CT-measured displacement in patients with fractures of the zygomaticomaxillary complex.

BACKGROUND: This prospective clinical study aimed to analyse the influence of displacement on duration and severity of symptoms of fractures of the zygomaticomaxillary complex. METHODS: 47 patients, who received surgical treatment of zygomaticomaxillary complex fractures at the Department of Oral and Maxillofacial Surgery/Plastic Surgery, University Hospital Jena were examined preoperatively, 1, 3 and 10 days as well as 6 months post-operation for ophthalmologic, occlusal and neurosensory changes. RESULTS: Preoperatively, periorbital haematoma and ooedema were present in 76.6% and 31.9% of the patients, which increased until day 1 post-op and decreased until the end of hospital stay. Preoperative diplopia was present in 83.0% of the patients and resolved postoperatively in all but 3 cases, in whom it persisted until end of the study. Occlusal disturbances and limited mouth opening were present in 21.3% of the patients and resolved by end of the study in all but 2 cases. Neither ophthalmologic nor occlusal changes correlated with the degree of displacement. Postoperatively no significant differences were detectable among the groups. In 44.8% of the patients neurosensory disturbances persisted until end of the follow-up. In the non-displaced fracture group none of the patients suffered from neurosensory disturbances at the 6-month follow-up. CONCLUSION: Although the degree of displacement has a significant impact on the incidence of sensory disturbances preoperatively, postoperatively no differences were observed between displaced and non-displaced fractures.

Histomorphometric and whole-genome expression analysis of peri-implant soft tissue healing: a comparison of flapless and open surgery.

PURPOSE: The structure of peri-implant soft tissue that is regenerated after flapless and flap surgery has been shown to differ. However, its underlying mechanisms are relatively unknown. The present study sought to identify differences in the inflammatory cell infiltration and expression of gene transcripts during transmucosal healing between the two approaches with two different implant designs. MATERIALS AND METHODS: All mandibular premolars were removed from 12 minipigs. One month later, four implants (two NobelReplace Tapered Groovy and two NobelPerfect Groovy, Nobel Biocare) were placed in each quadrant. One quadrant was randomized to flapless insertion, while the other was chosen for flap surgery in each animal. Following 1, 2, 4, and 12 weeks of transmucosal implant healing, biopsy specimens were retrieved from the peri-implant soft tissue according to a standardized procedure to avoid crossover effects. Samples were subjected to a leukocyte count and a gene expression analysis. RESULTS: When the flapless placement technique was used, leukocyte influx in the peri-implant soft tissue was significantly smaller compared to open surgery for both implant designs. Gene expression analysis revealed significant overexpression of molecules associated with detoxification and reepithelialization in the flapless group. In contrast, myofibroblast-associated gene transcripts were significantly enriched in the flap surgery group. CONCLUSIONS: The present data indicate perpetuation of inflammatory reactions as well as increased fibrotic scar tissue deposition in the peri-implant area following implant placement by the flap approach. Flapless implant insertion results in less inflammation and early reepithelialization, providing the potential for the formation of a fully functioning as well as esthetically preferable peri-implant soft tissue collar.